Does dual trigger improve euploidy rate in normoresponder? A cross-sectional study

Abstract Background With the introduction of the dual triggering-gonadotropin-releasing hormone (GnRH) analog and recombinant human chorionic gonadotropin (hCG) combination, women with a history of low mature oocyte proportion and empty follicle syndrome were shown to benefit from the dual trigger. Objective To investigate whether dual triggering of oocyte maturation with a GnRH agonist (GnRHa) combined with hCG can affect the euploidy rate and improve in vitro fertilization outcomes for normoresponder women. Materials and Methods In this cross-sectional study, 494 women who underwent controlled ovarian stimulation with hCG (n = 274) or dual triggering (hCG+GnRHa, n = 220) at Acibadem Maslak hospital, Assisted Reproductive Unit, from January 2019-2022 were enrolled in this study. Preimplantation genetic testing for aneuploidy was performed on all participants. Results Both groups had similar baseline and clinical characteristics. Of the 881 embryos biopsied, 312 (35.4%) were reported as euploid in the hCG trigger group; in the dual trigger group, 186 (29.8%) of 623 screening embryos were reported as euploid. The hCG group had a higher euploidy rate per biopsied embryo, although the difference was not statistically significant (31.4 ± 26.5 vs. 26.5 ± 33.3, p > 0.05). Conclusion In normoresponders, adding GnRHa for final follicular maturation to hCG did not improve the euploidy rate.


Introduction
During the normal physiological process, Due to its similarity to LH in biological activity and molecular structure in assisted reproductive technology (ART) cycles, human chorionic gonadotropin (hCG) is administered to trigger the final stage of follicular maturation to increase LH-like activity (2,3). The increase in LH receptors is significant in preparing the mature follicle for the LH surge that triggers ovulation and subsequent luteinization of the GCs. However, hCG has no FSH receptor activity. An FSH surge induces the formation of LH receptors on GCs. FSH promotes the resumption of oocyte meiosis and cumulus expansion (4). The first study described a gonadotropin-releasing hormone (GnRH) analog that induces a surge for final oocyte maturation, resembling the spontaneous mid-cycle surge to increase both FSH and LH serum levels (5).
Lower levels of epidermal growth factors, such as peptide amphiregulin in follicular fluid, and higher mRNA amphiregulin expression in GC, have been reported with the use of GnRH agonist (GnRHa) triggers, as compared to hCG triggers. These changes have been associated with improved markers of embryo quality and fertilization rates (6,7). Today, GnRHa is commonly referred to as an emergency treatment to eliminate ovarian hyperstimulation syndrome.
Following the introduction of the concept of dual triggering-GnRH analog and recombinant hCG combination in 2018 (8), women with a history of low-mature oocyte proportion and empty follicle syndrome were shown to benefit from dual triggering (9)(10)(11)(12)(13).
Evidence suggests that dual triggering decreases conexin43 gene expression (14), while increasing epiregulin and amphiregulin expressions in the GCs, thus improving oocyte and embryo quality (6,15). Another topic of debate is how dual triggering affects the rate of euploidy.
In a limited number of studies comparing the effect of GnRH analog and hCG on the euploidy rate, the euploidy rate was similar (16,17). According to a recent comprehensive review and meta-analyses, dual triggering yielded more retrieved and mature oocytes and a greater clinical pregnancy rate than hCG alone; therefore, it is crucial to investigate whether dual trigger could improve blastocyst euploidy rates, which could account for better results (18,19).
This study investigated whether dual triggering of oocyte maturation by a GnRH analog combined with hCG would affect euploidy rates and improve in vitro fertilization (IVF) outcomes for normoresponders in GnRH antagonist cycles.

Materials and Methods
This cross-sectional study was conducted at

IVF protocol
All participants underwent a short protocol.

Outcome measures
The primary outcome measure was the embryo euploidy ratio (number of euploid embryos per total number of biopsied embryos). Secondarily, the outcome measure was the number of retrieved oocytes, MII oocytes, the cleavage stage of embryos, and the euploidy ratio per oocyte (number of euploid embryos per total oocyte retrieved).

Ethical considerations
The study was approved by the Ethics Committee of Acibadem University Medical

Statistical analysis
The statistical analysis of the data was

Discussion
The major objective was to investigate whether a dual trigger for follicular maturation would not associated with embryo formation rates, survival, or embryo quality in hyperresponder women (25).
After introducing the dual trigger concept, the dual trigger application was offered to overcome suboptimal/poor prognosis or previous abnormal final follicular maturation (13,24,26). The studies showed that dual trigger increases mature oocyte recovery in women with a previous history of low mature oocyte retrieval (9,13). In addition, poor responders with dual triggering had more topquality embryos than hCG alone (27

Conclusion
In the present study, the euploidy rate per retrieved oocyte and blastulation rate was higher in the hCG trigger. For normoresponder women, although trigger modality did not affect euploidy rates per biopsied embryo. The euploidy rate was not improved by adding GnRHa. However, more research is needed to confirm and reinforce these conclusions.